Photoacoustic imaging (PAI) makes use of infrared-induced ultrasound for constructing an image of an organ or tissue inside the body. In this process, a short infrared pulse, typically 5-10 ns in width, is used to illuminate the organ or tissue. Upon absorption of infrared energy, the tissue heats up and expands. This instantaneous tissue expansion generates ultrasound, which is received by an ultrasound transducer for image formation. Photoacoustic imaging makes use of the difference of infrared absorption rate of different tissues and may provide better image contrast than pulse-echo ultrasound imaging. Due to the high infrared absorption rate of hemoglobin, a photoacoustic imaging process may be useful in imaging blood-containing organs/tissue and may therefore be useful for identifying disease symptoms related to blood, including early-stage tumors or internal bleeding.
As a promising new technology, photoacoustic imaging is gaining ground in clinical use and has been proved to be useful in providing critical diagnostic information (mainly due to its blood “seeing” capability) not available from traditional medical imaging modalities including X-ray and pulse-echo ultrasound. Currently, one common practice of performing photoacoustic imaging uses a laser light source for tissue illumination and a separately positioned ultrasound transducer for receiving the ultrasound transmitted from the infrared-stimulated tissue. The laser light source, the ultrasonic transducer, and the target tissue are manually aligned in order to obtain the maximum ultrasound signal. While useful as a laboratory platform, this setup is not suitable for an end user like a medical doctor for general clinical use.
It may be desirable to provide a photoacoustic imaging device that integrates a broad-area infrared light source with a microelectromechanical systems-based ultrasonic transducer array in a package for medical imaging. Similar to a camera with a built-in flash light, the relative position between the infrared light source and the ultrasonic transducers on the integrated device may be accurately aligned with both devices being aimed at the target direction. Thus, the integrated photoacoustic imaging device can be placed on the skin of the patient for imaging, and no infrared light source to ultrasound transducer alignment is needed.
It may be desirable to provide the integrated imaging device with an integrated front-end signal-processing circuit so that the device can provide portable, real-time, three-dimensional photoacoustic imaging of an organ or tissue for clinical use. It may be desirable to display the three-dimensional images acquired by the imaging device in real time and/or to store the images, for example, in a personal computer, for future review.
It may be desirable to provide the integrated photoacoustic imaging device with pulse-echo ultrasound imaging in parallel with the photoacoustic imaging so as to offer complementary diagnostic information.
PAI is also gaining ground as a potential replacement for mammography. Breast cancer is a cancer that starts in the cells of the breast. Worldwide, amongst both sexes combined, breast cancer is the second most common type of cancer after lung cancer and the fifth most common cause of cancer death. Women in the United States have the highest incidence rates of breast cancer in the world. Among women in the US, breast cancer is the most common cancer and the second-most common cause of cancer death (after lung cancer). In 2007, breast cancer was expected to cause 40,910 deaths in the US (7% of cancer deaths; almost 2% of all deaths).
While mammography is the only breast cancer screening method that has been shown to save lives, it is not perfect and has its limitations. First, estimates of the numbers of cancers missed (false-negative) by mammography are usually around 10%-20%. Mammography cannot detect small tumors with diameters less than 4 mm at their earliest stages. Tumors of early stage are generally soft and embedded in soft tissue, so the cancer is easily hidden by other dense tissue in the breast and even after retrospective review of the mammogram, cannot be seen. Also, because the X-ray contrast between the early tumor tissue and normal tissue types is low, it is hard for the mammography to detect the early stage tumors. In order to be reliably detected by traditional X-ray-based mammography, the tumor must be large and have a high density. The technique is further challenged by the age of the woman; younger women have denser breast tissue, making masses harder to detect. Furthermore, one form of breast cancer, lobular cancer, has a growth pattern that produces shadows on the mammogram which are indistinguishable from normal breast tissue.
Second, mammography often fails to differentiate conclusively between malignant and benign masses (false positive) which will cause women to undergo unnecessary medical intervention and undue stress. It helps to know these approximate statistics: of every 1,000 U.S. women who are screened, about 7% (70) will be called back for a diagnostic session (although some studies estimate the number closer to 10%-15%). About 10 of these will be referred for a biopsy; the remaining 60 are found to be of benign cause. Of the 10 referred for biopsy, about 3.5 will have a cancer and 6.5 will not. Of the 3.5 who do have cancer, about 2 have a low stage cancer that will be essentially cured after treatment.
Breast cancer has a very characteristic pathophysiological profile. A malignancy is highly vascularized. When a tumor is malignant, it develops rapidly and needs a lot of nourishment and oxygen. To supply these components, tumors develop a microcirculation network through a process called angiogenesis. This network helps the tumor withstand an immune system attack and continue its aggressive growth. The presence of this network also means that the tumor will have a concentration of blood that ranges from two to six times the amount expected in normal breast tissue. The second differentiating characteristic of a breast tumor is a function of the tumor's hunger for oxygen. The blood in the tumor is oxygen depleted, or hypoxic. Oxygenated blood has a different infrared absorption coefficient than hypoxic blood. Finally, visualizing the mass accurately gives the best indication of its shape, which is another clue to malignancy. A smooth, symmetrical shape holds the best news, while an irregularly shaped mass indicates trouble. When the shape is very ugly, it is a strong indication of malignancy. When it is round or elliptical, the mass has been encapsulated by the immune system, indicating a benign tumor. While irregular blood vessel distribution and blood oxygen concentration provide the surest indication of breast cancer, conventional X-ray-based mammography or ultrasound imaging cannot distinguish blood from tissue and therefore would miss this valuable diagnostic information. While magnetic resonance imaging (MRI) is capable of capturing the image of blood, the equipment and operation cost of MRI is too expensive for regular annual breast screenings, which are recommended for women above the age of 40.
Photoacoustic imaging provides an affordable solution to this problem. PAI uses a short pulse of light to generate acoustic waves that are used to form an image. In this process, the target object is flashed with a laser pulse on the order of 5 nanoseconds, leading to optical absorption (typically a fraction of a degree Celsius) and thermo-elastic expansion. This expansion generates ultrasound, which can be detected by an ultrasound transducer or an array of receivers to form a three-dimensional (3-D) image. Whereas traditional pulse-echo ultrasound imaging has low contrast in soft tissue due to similar acoustic impedances, PAI benefits from high optical contrast combined with excellent spatial resolution determined primarily by the ultrasound wavelength, approaching cellular resolution. Contrast in PAI depends primarily on the optical wavelength and absorption spectrum of the tissue. Thus, PAI provides an appreciably higher contrast than pulse-echo ultrasonic imaging. Moreover, when the light source is tuned to the near infrared, PAI can be used to form an image well over a centimeter into tissue. One-way propagation of ultrasound is used to carry the information back to the ultrasound receiver(s), and conventional beamforming based on time delays can be used to create an image.
For photoacoustic imaging of live human or animal tissue with red blood cells, hemoglobin provides significant help in boosting the contrast ratio. Hemoglobin has a very high optical contrast in the visible and infrared spectra. As a result, high-contrast imaging of blood containing structures in tissue such as tumors or blood vessel is one of the unique advantages of PAI. Due to making use of this blood concentration/content related optical absorption, PAI is exceptionally useful for identifying diseases/abnormalities related to blood, such as internal bleeding from stroke or early-stage cancer. Doctors can use PAI to recognize many problems that are difficult to identify using conventional diagnostic techniques, such as pulse echo ultrasound, x-ray or magnetic resonance (MR).
Compared to other techniques, PAI is a safe process that uses nonionizing radiation and fluences within standards set by ANSI and could provide 3-D images with high resolution and contrast. In addition to viewing anatomical structure, photoacoustic imaging is capable of detecting composition of tissue and functional activities of an organ based on blood-related infrared absorption rate difference and sensitivity of the optical spectrum of hemoglobin to oxygenation saturation.
Photoacoustic imaging forms an image of an object using ultrasound transmitted from the object in a light induced heating process. Involving interactions between photons, ultrasound, and an object, photoacoustic imaging is non-ionizing and capable of viewing anatomical structures in tissue with improved image contrast than that from pulse-echo ultrasound imaging. Photoacoustic imaging works by flashing a short-pulsed near-infrared laser at low energy onto a target tissue. The long wavelength of near infrared light allows light to penetrate deep into the tissue. As the light is absorbed by tissue, the tissue heats up and expands through a process called rapid thermo-elastic expansion. This instantaneous tissue expansion creates ultrasonic waves which can be received by an ultrasound detector array. The received acoustic signals can be interpreted using beam-forming algorithms to generate 2-D or 3-D images of the target tissue. With contrast based on optical absorption, and sub-mm spatial resolution, photoacoustic imaging offers attractive attributes for imaging biological tissue. When a near-infrared (NIR) laser source is used, it has an added benefit of excellent penetration into biological tissue of several centimeters.
Compared to traditional pulse-echo ultrasound imaging, photoacoustic imaging provides optical contrast with good penetration and high spatial resolution, making it an attractive tool for non-invasive applications in medical diagnosis, especially for unique applications such as high blood concentration identification. By combining with intravascular ultrasound (IVUS) imaging, photoacoustic imaging can visualize both morphological and functional changes of the vulnerable plagues in the vessel, and thus can be used for invasive applications.
Photoacoustic imaging is a promising new technology that will likely find its way soon to the clinical arena for human use. One of the current limitations of PAI for general clinical use is developing the technology and hardware that would provide fast, real-time anatomical or functional images. This is critical to extend PAI to be used on. Currently one of the most common practices for photoacoustic imaging is using a near-infrared laser, such a Q-switched Nd:YAG laser or a laser diode coupled to an optical fiber or a lens, to illumine the target biological object. A separately located ultrasonic transducer (or an array of receivers) is used to detect the ultrasound emitted by the tissue. Manual alignments between the infrared source, the ultrasound transducer, and the target tissue are needed. Manual alignment/adjustment is time consuming and does not always produce satisfactory results. In addition, few existing systems allow for full parallel receive that would provide a 3D image from a single laser pulse.
Medical doctors would benefit most from a simple system and device that provides real-time PAI. A system that integrates both the light illumination and ultrasound receiving array together would facilitate PAI, especially for human use.
The current photoacoustic imaging mainly relies on single piezoelectric transducer for the ultrasound detection. However, the device performance of the piezoelectric ultrasonic transducer in medical applications is limited by the material properties and related electrical and acoustic impedance match issues. The fabrication of piezoelectric transducer array requires meticulous handcrafting. Relatively recently, capacitive micromachined ultrasonic transducers (CMUTs) have emerged as a promising alternative. Extensive research on the fabrication and modeling of CMUTs began in the early 1990s. Except for the inherent advantages such as the broader bandwidth, higher sensitivity over piezoelectric counterpart, CMUT technology provides a promising approach to manufacturing densely populated array and realization of high-frequency imaging probes using standard micro-fabrication techniques such as photolithography and thin film deposition. This high frequency CMUT probe can be the answer to the demand of high-resolution imaging system for invasive applications such as the combination of photoacoustic and intravascular imaging system.
It may be desirable to continue development of a miniature capacitive micromachined ultrasonic transducer (CMUT) array for photoacoustic imaging (PAI). As a minimally invasive imager, such a device may be capable of receiving relatively weak ultrasound signals that are difficult to access with non-invasive transducers and may be useful for acquiring photoacoustic images of biological structures deep inside the tissue or inside an organ.
It may further be desirable to fabricate a CMUT imager probe using a two-layer polysilicon surface micromachining process, followed by a double-sided deep silicon etching process for shaping the silicon substrate into a thin probes. It maybe desirable to develop new CMUT structures for an implantable imager probe, aiming at reducing the effective gap height and the driving voltage, as well as alleviating the charging trap effect.
This disclosure solves one or more of the aforesaid problems with a photoacoustic imaging device that integrates a broad-area infrared light source with a microelectromechanical systems-based ultrasonic transducer array.